Neurofibrillary tangles composed of tau protein are key lesions in such neurodegenerative diseases as Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia and parkinsonisms linked to chromsome 17 (FTDP-17). We recently generated a novel mouse model that expresses human tau containing an FTDP-17 mutation, P301 L. These mice develop tau neurofibrillary tangles, neuronal loss, amyotrophy, and behavioral and motor deficits. The tau neuropathology in these mice is strikingly similar to the neurofibrillary tangles observed in human tauopathies. Although our tau model makes it possible to study the earliest stages of neurodegeneration associated with tau dysfunction, these mice cannot address whether continuous mutant tau expression is essential for the development and progression of neurofibrillary pathology. In this grant, we propose utilizing the tetracycline-regulated system of gene expression to generate mice that conditionally express P301L tau. These animals will allow us to control the timing and duration of tau expression and thereby permit us to answer questions regarding the development and progression of tau neuropathology and biochemical changes. The ability to control tau expression in these animals will help determine if uninterrupted expression of pathogenic tau is required for formation of tau-related neuropathological and biochemical changes. Furthermore, we can determine if expression of the pathogenic tau in aged mice is sufficient to produce accelerated tau neuropathology and biochemical changes to investigate the role of aging in tauopathies. Finally, these conditional tau animals will allow us to determine if repression of tau expression can abrogate pre-existing tau pathology and biochemical changes.